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It’s a pig’s life

By Andy Coghlan

WITHIN a few years, the first human will have his or her dying heart or
kidney replaced with a healthy one from a pig—transplant scientists are
sure of it. But even if the pioneering surgery buys the patient a longer life,
it could be at a price. Quite apart from having to take drugs to stop their
bodies rejecting the foreign organ, patients may face social exile as a
precondition for treatment.

No more sex, at least for a year or two. No babies once the sex curfew has
been lifted. No visits to anyone other than close family and friends. And an
indefinite ban on social outings.

Too far-fetched to be true? Senior figures in key agencies such as the US
Food and Drug Administration (FDA) don’t think so. Such a scenario could form
part of their plans to ensure that recipients of pig organs don’t unleash
dangerous new viruses on an unsuspecting world. The high levels of immune
suppression required to prevent rejection may actually ease transmission of pig
viruses. And these fears persist in spite of new findings which suggest that
transplant patients will be safe from such viruses.

Kaz Paradis and his team at Imutran, the Cambridge-based company developing
pig hearts and kidneys for transplant, screened tissue samples from 160 patients
around the world treated with live pig tissue. Blood from 131 had been filtered
through live pig tissue during operations. The remaining 29 had received grafts
of pig tissue.

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Despite earlier experiments when such viruses infected human cells in the
lab, Paradis’s team found no evidence that porcine endogenous retroviruses
(PERVs) had infected any of the patients (New Scientist, 21 August, p
20). Corinne Savill, chief executive officer of Imutran, a subsidiary of the
Basel-based pharmaceuticals giant Novartis, says the first organs could be
transplanted within two years.

Protecting the public

The company is now experimenting with primates to fine-tune the lifelong drug
regimes transplant patients would need to prevent rejection of their pig organs.
Providing Imutran gains regulatory approval, human trials could begin on a group
of around 10 patients, probably in Canada.

But despite Imutran’s optimism, independent experts such as Jonathan Stoye,
who studies pig viruses at Britain’s National Institute of Medical Research in
Mill Hill, London, say public safety is far from assured. Stoye concedes that
studies so far suggest that the risks PERVs pose are unlikely to outweigh the
benefits for a transplant patient. “But the question about broader risks to the
general population remains unanswered,” he says. Even Imutran acknowledges this
possibility. “The concern people have raised is not the safety of the
recipient,” says Savill. “It’s whether there’s a possibility of
transmission.”

Regulatory agencies around the world are already developing guidelines on how
to quarantine pioneers who receive the first transplants. A working group set up
by the UK Xenotransplantation Interim Regulatory Authority (XIRA)—which
vets applications for xenotransplant trials—has prepared a confidential
draft report on monitoring and surveillance for patients. In the US, federal
agencies that oversee transplants are revising their guidelines to accommodate
the first recipients of xenotransplants, Philip Noguchi, director of the FDA’s
division of cellular and gene therapies told New Scientist. “We
understand those concerns [about viral infections] and intend to address them,”
he says. “We must know the status of patients after they’ve undergone
transplants.”

Two years ago, 10 patients waiting for transplants at Northwestern University
Medical School in Chicago were about to be hooked up to pig livers for short
periods (New Scientist, 18 October 1997, p 4) .But the FDA
pulled the plug at the last moment as fears about PERVs mounted.

Even if “quarantine“regulations are agreed, enforcing them could prove
very tough. Stoye’s greatest fear is that if the treatments fail, patients will
see no reason to stick to the rules and go AWOL. “It’s a very difficult issue,
and there’s no law that would allow [compulsory isolation] of recipients or
anyone else they infect,” says Stoye. “Any participation in a clinical trial is
purely voluntary, so if you say you must follow these people indefinitely, and
this is an absolute requirement of the treatment, you have a real problem,” he
says.

People who currently receive human organ transplants are not supposed to give
blood, and Stoye expects the same rule to apply to recipients of xenografts.
“But you can’t force people not to have sex, or sterilise people—these are
not on,” he says.

Savill says the XIRA has invited Imutran to discuss the issue. “You would do
testing at fairly regular intervals, and for the first recipients, you would not
advise having any children until more is known about the therapy. But that’s a
condition of many new treatments,” she says.

Even before patients get near the operating table, Imutran has problems of a
more practical nature to overcome. The most pressing task facing Savill and her
colleagues is finding the right mix of powerful drugs to prevent patients’
immune systems destroying their new organs.

Xenografts present a special problem. Not only do they have to contend with T
cells, like a new human organ, but they are also a target for antibodies made by
B cells. This means dampening down not just one but two arms of the immune
system to prevent vascular rejection.

The company hopes that a new class of drugs currently under development
called macrolides will do the trick, since they dampen both responses. But
critics of xenotransplants say that this high level of immunosuppression could
make it easier for pig viruses to infect human cells.

Proponents of xenotransplantation point to encouraging data emerging from
other trials that involve small implants of animal tissue or other limited
exposure (New Scientist, 8 August 1998, p4). Diacrin of Charlestown,
Massachusetts, for example, has had some success implanting brain cells from pig
fetuses into the brains of patients with Parkinson’s disease and Huntington’s
disease. Circe Biomedical of Lexington, Massachusetts, continues to successfully
cleanse the blood of patients with liver failure by passing it through a device
containing pig liver cells. The absence of PERV transmission in these
experiments will reassure advocates of xenotransplantation.

Desperate need

But Gill Langley of the Hadwen Trust for Humane Research in Hitchin,
Hertfordshire, believes replacing an entire organ will be far more risky than
anything tried so far. “The organ is expected to reside in intimate contact with
the patient’s tissues and blood for months or years at a time,” she says.
However, because organs are so desperately needed, Stoye does support trials of
complete pig organ transplants at some stage—albeit extremely cautious
ones.

While individuals in desperate need of a transplant stand to gain, the
theoretical risk of a public health disaster cannot be discounted. So why risk
xenotransplants when emerging stem cell technology could create substitute
organs from a patient’s own cells? Some researchers hope these cells, which have
the potential to become “customised organs”, will one day provide an
inexhaustible supply of human organs that will do away with the need for
immunosuppressive drugs. “Under perfect circumstances, I would want to use human
organs, but that’s science fiction,” says Jon Allen, a virologist at the
Southwest Foundation for Biomedical Research in San Antonio, Texas. “There’s a
much greater chance that xenotransplantation may fill that niche for the next 10
years.”

For now at least, we may have to tolerate a degree of human quarantine if we
want to save the lives of people with failing organs, as well as safeguarding
the health of everyone else.